The present invention relates to methods of making indazoles and more particularly relates to methods of making indazoles which avoid unwanted by-products and results in enantiomerically pure final pharmaceutically active products.
WO 98/30548 (Yamanouchi) shows the utility of 1-(aminoalkyl)indazoles for treating CNS diseases. The route of synthesis involves the reaction of various indazoles, having substituents only in the benzene ring, with alkylating agents. It is well known that such alkylation of indazoles always gives about a 1:1 mixture of isomeric 1- and 2-alkylindazoles. See, generally, Song and Yee, Organic Letters, vol. 2, page 519 (2000). Therefore about half of the reaction material is wasted due to the formation of the undesired 2-alkylindazole which must be separated by chromatography or other technique. The isolated 1-alkylindazole is then further modified to provide the target 1-(aminoalkyl)indazole.
Fischer and Tafel, Justus Liebigs Annalen der Chemie, vol. 227, p. 334 (1885) report nitrosation of 2′-ethylaminoacetophenone with sodium nitrite and the reduction of the resulting nitrosamine with zinc to yield 1-ethyl-3-methylindazole. Use of isoamyl nitrite instead of sodium nitrite for an analogous nitrosation is discussed in Applegate and Turnbull, Synthesis, p. 1011 (1988). McGeachin, Canadian Journal of Chemistry, vol. 44, p. 2323 (1966) reports nitrosation of a 2-aminobenzaldehyde wherein the amino group is substituted with a nonhydroxylic C23H18N3O group, for the purpose of verification of chemical structure. The resulting nitrosamine was reduced with zinc forming a very specific indazole, for the purpose of further verification of chemical structure.
Monoalkylhydrazines react with benzophenones or acetophenones having ortho leaving groups (e.g., halide or mesylate) to give 1-alkylindazoles substituted at the 3-position as reported in Caron and Vazquez, Synthesis, p. 588 (1999). The analogous conversion of benzaldehydes to 3-unsubstituted indazoles requires forcing conditions unsuitable for scaleup. See Halley and Sava, Synthetic Communications, vol.27, p. 1199 (1997).
Suwinski and Walczak, Polish Journal of Chemistry, vol. 59, p. 521 (1985), report cyclization of 2-aminobenzaldoxime hemisulfate to give indazole. The inventors attempted to extend this method to a 2-alkylaminobenzaldoxime hemisulfate, but the desired 1-alkylindazole was not obtained and instead the unwanted nitrile or the free oxime was obtained. An analogous cyclization of oxime acetates, demonstrated only for forming 3-substituted indazoles, employs conditions poorly suited for scaleup as shown in Brown et al., Journal of Medicinal Chemistry, vol. 35, p. 2419 (1992). Cyclization of 2-acylaminobenzaldoxime derivatives yields 1-acylindazoles (von Auwers and Frese, Justus Liebigs Annalen der Chemie, vol. 450, p. 290 (1926)) but these do not provide 1-alkylindazoles upon reduction, the 1-unsubstituted indazole being formed instead. See Al-Khamees and Grayshan, Journal of the Chemical Society, Perkin Trans. I, p. 2001 (1985). A known synthesis of 1,3-dialkylindazoles from 1,3-dialkylindoles involves (1) oxidative cleavage of the 1,3-dialkylindazole to give the 2-(N-alkylformamido)aryl alkyl ketone; (2) ketoxime formation with concurrent N-deformylation; (3) O-acetylation; and (4) heating the resulting ketoxime acetate at 170–200° C. in the melt, under vacuum. See Matassa et al., J. Med. Chem., vol. 33, page 1781 (1990); and Brown et al., J. Med. Chem., vol. 35, page 2419 (1992). This method has not been demonstrated for aldoximes, required for the synthesis of 3-unsubstituted indazoles. Furthermore, the in vacuo thermolysis step has been reported on a maximal 1.3-gram scale, and would present experimental difficulties on a larger preparative scale.
Accordingly, there is a need to provide processes to manufacture 1-(aminoalkyl)indazoles which avoid undesired isomers and which are capable of producing large quantities of the desired compound.
All patents, patent applications, and publications referenced in this application are incorporated in their entirety and form a part of the present application.